Reservoir Device for Intraocular Drug Delivery

ABSTRACT

A delivery device that allows for the sustained release of an agent, particularly useful for the sustained release of a therapeutic agent to limited access regions, such as the posterior chamber of the eye and inner ear. The delivery device is minimally invasive, refillable and may be easily fixed to the treatment area. The delivery device includes a hollow body with an inlet port at its proximal end for insertion of the agent, a reservoir for holding the agent and a delivery mechanism for the sustained delivery of the agent from the reservoir to the patient.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is a Continuation of co-pending U.S. patentapplication Ser. No. 15/060,532, filed Mar. 3, 2016, which is acontinuation of U.S. patent application Ser. No. 14/268,723, filed May2, 2014, now abandoned, which is a continuation of U.S. patentapplication Ser. No. 13/942,610, filed Jul. 15, 2013, now U.S. Pat. No.9,180,046, issued Nov. 10, 2015, which is a continuation of U.S. patentapplication Ser. No. 12/979,185, filed Dec. 27, 2010, now U.S. Pat. No.8,486,052, issued Jul. 16, 2013, which is a Divisional of U.S. patentapplication Ser. No. 10/171,406, filed Jun. 12, 2002, now U.S. Pat. No.7,883,717, issued Feb. 8, 2011, which claims the benefit of U.S.Provisional Application Ser. No. 60/297,499, filed Jun. 12, 2001. Thepriority of the filing dates is hereby claimed, and the disclosures ofeach of the above-mentioned patent applications are hereby incorporatedby reference in their entirety.

BACKGROUND

The present invention relates to improved delivery devices and methodsof use. More particularly, the present invention relates to minimallyinvasive, refillable, sustained release delivery devices particularlysuitable for the delivery of therapeutic agents to limited accessregions, such as the posterior chamber of the eye.

The delivery of drugs to the eye presents many challenges. The ocularabsorption of systemically administered pharmacologic agents is limitedby the blood ocular barrier, namely the tight junctions of the retinalpigment epithelium and vascular endothelial cells. High systemic dosescan penetrate this blood ocular barrier in relatively small amounts, butexpose the patient to the risk of systemic toxicity. Topical delivery ofdrugs often results in limited ocular absorption due to the complexhydrophobic/hydrophilic properties of the cornea and sclera.Additionally, topical agents are mechanically removed by the blinkmechanism such that only approximately 15% of a single drop is absorbed.Diffusion of topically administered drugs to the posterior chamberoccurs, but often at sub-therapeutic levels. Intravitreal injection ofdrugs is an effective means of delivering a drug to the posteriorsegment in high concentrations. However, these repeated intraocularinjections carry the risk of infection, hemorrhage and retinaldetachment. Patients also find this procedure somewhat difficult toendure.

Local sustained delivery of therapeutics to the posterior chamber iscritical in managing several chronic diseases of the eye. To addressthis need, several drug delivery devices have been developed forintraocular insertion into the vitreous region of the eye.

U.S. Pat. No. 4,300,557, for example, describes an intraocular implantin the form of a silicone capsule which can be filled with a drug to bedelivered. The capsule is inserted in the vitreous region of the eye bymaking an incision in the eye, inserting the capsule and closing theincision. The capsule remains in place for a period of time and may beremoved by making a second surgical incision into the eye and retrievingthe device. The capsule has an attached tube which passes through thesurface of the eye and extends outward from the eye useful for thesubsequent injection of a drug. While in the vitreous, the device is notanchored and may move about freely.

U.S. Pat. No. 5,378,475 (often referred to as Vitrasert) describes adevice 15 which has been developed for insertion in the vitreous regionof the eye, and is described in T. J. Smith et al., Sustained-ReleaseGanciclovir, Arch. Ophthalmol, 110, 255-258 (1992) and G. E. Sanborn, etal., Sustained-Release Ganciclovir Therapy for Treatment ofCytomegalovirus Retinitis. Use of an Intravitreal Device, Arch.Ophthalmol, 110, 188-195 (1992). This device consists of an inner coreof pharmacologic agent surrounded by two coatings with differentpermeabilities. Drug diffuses through a small opening in one of thesecoatings achieving near-order release kinetics. It is implanted in theregion of the pars plana through a 3.5-5.0 mm scleral incision. Theimplant must be removed and replaced every 6 months in the operatingroom as the drug becomes depleted. There is an approximately 25%complication rate from these procedures. The device is membranediffusion drug delivery system that relies on EVA/PVA polymers tomediate release rate. Thus, many agents cannot be effectively deliveredfrom such a system because their permeation rate through the ratecontrolling material of the system is too small to produce a usefuleffect. Other agents cannot be satisfactorily delivered by diffusionaldevices because of a particular chemical characteristic of the agent.This includes salts, because of their ionic character, and unstablepolar compounds that cannot be formulated into a composition suitablefor storage and delivery from such systems.

U.S. Pat. No. 5,098,443 describes a series of C-shaped rings that areinserted through incisions made in the eye wall or sutured around theglobe of the eye. These rings may be formed from biodegradable polymerscontaining microparticles of drug. Alternatively, the implant may be inthe form of a hollow flexible polymeric cocoon with the drug disposedtherewithin for slow release by osmosis. No anchoring device isdescribed.

U.S. Pat. No. 5,466,233 describes a tack for intraocular drug delivery.This device has an end that is positioned in the vitreous cavity whilethe head remains external to the eye and abuts the scleral surface. Thedrug is contained in the vitreous end of the device and could becontained within a biodegradable or nonbiodegradable scaffold.Alternatively, the device may have a hollow core filled with a drug thatcould diffuse through the wall of the tack into the eye. This core couldbe refillable. The head of the tack may further have a suture hole foranchoring the sclera.

While intraocular devices exist which allow delivery of therapeuticagents to the eye, a need still remains for a device which accomplishescontrolled, sustained delivery to the posterior chamber, is implantableand removable without requiring long full thickness scleral incisions,does not cause undue patient irritation or discomfort, is stable withinthe vitreous region of the eye, is refillable and dose titratable, andis capable of delivering a wide range of small molecule, gene andprotein therapeutics.

SUMMARY

The present invention provides a delivery device and methods of use.More particularly, the present invention relates to a sustained releasedelivery device that is minimally invasive and refillable. The deliverydevice of the present invention is particularly suitable for thedelivery of therapeutic agents to the posterior chamber of the eye andother limited access regions.

An exemplary embodiment of the delivery device includes a reservoirhaving an inlet port at its proximal end for insertion of the agent. Ascleral hub, or similar fixation element, may further be located nearthe proximal end for suturing or otherwise securing the device at adesired location. The agent inserted into the reservoir through theinlet port is delivered to a treatment area by a delivery mechanismlocated along the reservoir and/or at the distal end of the reservoir.For example, in one embodiment, the agent may be delivered through thereservoir by, for example, forming the reservoir of a material that ispermeable to the agent or, for example, providing one or more aperturesin the reservoir through which the agent may flow. In anotherembodiment, the delivery mechanism is located at the distal end of thereservoir by, for example, forming the distal end of the reservoir of asemi-permeable membrane or providing one or more apertures in the distalend of the reservoir. The reservoir is preferably fabricated of apliable material that allows the reservoir to be compressed forinsertion through a small incision. Once inside the incision, thereservoir may automatically unfold and/or as agent is injected throughthe inlet port, the reservoir may unfold as it is filled with the agent.

The drug delivery device may further include a hollow body or tubeinside the reservoir, wherein the proximal end of the hollow body ortube forms the inlet port. In this embodiment, hollow body or tube mayprovide structural rigidity that facilitates insertion of the devicethrough a small incision. The reservoir covers at least a portion of thelength of the hollow body or tube and is preferably pliable so that itmay be folded, rolled and/or compressed about the hollow body or tube toenable insertion of the device through a small incision not much largerthan the size of the hollow body or tube. At least one aperture in thehollow body or tube provides communication between the contents of thehollow body or tube and the reservoir such that, as the agent isinserted through the inlet port, it travels through the hollow body ortube, through the aperture(s) and into the reservoir. As the agent fillsthe reservoir, the reservoir unfolds. In one embodiment, the distal endof the hollow body or tube extends outside the reservoir and forms adelivery port through which the agent is delivered to the patient. Inanother embodiment, the therapeutic agent is delivered to the patientthrough the reservoir by, for example, forming the reservoir of amaterial that is permeable to the agent or, for example, providing oneor more apertures in the reservoir through which agent may flow. Ascleral hub, or similar fixation element, may further be located nearthe proximal end of the hollow body or tube for suturing or otherwisesecuring the device at a desired location.

Methods for the delivery of an agent are also disclosed. In particular,the methods involve delivery of agents to the eye to treat a variety ofocular conditions such as, for example, retinal detachment, vascularocclusions, proliferative retinopathy, diabetic retinopathy,inflammations such as uveitis, choroiditis and retinitis, degenerativedisease, vascular diseases and various tumors including neoplasms.

The methods comprise making a small incision in the eye to provideaccess to the treatment site. The delivery device is provided in an“empty” state, with the reservoir empty and preferably compressedtightly as shown in FIG. 1 a. Compressing the reservoir is desirablesince it allows the delivery device to be passed through a smallincision that requires few or no sutures for closure. The deliverydevice is then inserted through the incision distal end first until thescleral hub or fixation mechanism abuts the incision. The scleral hub orfixation mechanism may then be sutured or secured to the sclera toassist in maintaining the device at the treatment site. Once inside theincision, the reservoir may automatically unfold. The therapeutic agentis then injected into the device through the inlet port by use of asyringe or similar mechanism containing with the agent. The agenttravels into the reservoir, thereby further unfolding the reservoir.Once reservoir is filled to a desired level, the syringe may bedisconnected from the inlet port and the inlet port closed. The agent isthen delivered to the patient either through a delivery port or throughthe reservoir. After delivery of the contents of the reservoir to thepatient, the device may be refilled for further delivery of agent orremoved. At the time of removal, the reservoir is preferably empty andcompressed, thereby allowing the device to be removed through a smallincision that requires few or no sutures for closure.

Depending on the particular application, the device may be designed todeliver a desired dose of agent at a particular rate, for example, byproviding various sized reservoirs, reservoirs with variouspermeabilities to the agent, delivery apertures or ports with smaller orlarger diameters and delivery ports with rate controlling covers.

The present delivery device and methods of use are minimally invasive.In particular, the delivery device has a small profile that allows it tobe inserted through a small opening. Such an insertion procedureeliminates the risks associated with more invasive surgery, and,further, enables such procedures to take place in an office setting.Also, the device can be removed from a small insertion site, requiringfew or no sutures for scleral closure. This is a dramatic improvementover state of the art technologies which require surgery for bothimplantation and removal.

Further, while many existing devices for ocular delivery incorporate thetherapeutic agent into the structure of the implant for release viadiffusion or bioerosion of the carrier, the delivery device of thepresent invention is a refillable device easily filled and refilled byinjection. This feature allows the physician to easily titrate dosage tothe need of the individual patient. Additionally, a single device may beused with a wide range of agents, because the present device avoidsimplantation of the agent into the structure of the device during themanufacturing process.

Still further, because release of the agent using the present deliverydevice is not necessarily membrane diffusion regulated, the presentdevice lends itself to the delivery of agents that do not readilypermeate through polymeric membranes, such as ionic drugs or proteins.

Other aspects and embodiments of the invention are discussed infra.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A illustrates an empty delivery device in accordance with anembodiment of the present invention.

FIG. 1B illustrates the delivery device of FIG. 1a holding an agent.

FIG. 2 depicts the final location of the device of FIGS. 1a and 1bwithin the eye.

FIG. 3 depicts the final location of the device within the eye inaccordance with another embodiment of the present invention.

FIG. 4A illustrates an empty delivery device in accordance with anotherembodiment of the present invention.

FIG. 4B illustrates the drug delivery device of FIG. 4a holding anagent.

FIG. 5 shows a cross-sectional schematic view of an eye illustrating one10 technique of pulling back of the conjunctiva to provide access intothe eye for insertion of the delivery device of the present invention.

DETAILED DESCRIPTION

Referring now to the various figures of the drawing, wherein likereference characters refer to like parts, there is shown various viewsof a delivery device 1, in accordance with the invention.

As shown in FIGS. 1-3, the delivery device 1 includes a reservoir 2having a proximal end 3 and a distal end 4. Located near the proximalend 3 of the reservoir 2 is an inlet port 5 for injection of a desiredagent into the reservoir 1. Agent injected through the inlet port 5 isdelivered to the treatment area through delivery mechanism 6.

The delivery device 1 may further include a hollow body or tube 10housed at least partially within the reservoir 2. The hollow body ortube 10 has a proximal end 11 and a distal end 12. Preferably, theproximal end 11 of the hollow body or tube 10 extends outside thereservoir 2, as shown in FIGS. 1-3, and serves as the inlet port 5through which the agent is injected into the device.

The materials used in fabricating the reservoir 2 are not particularlylimited, provided these materials are biocompatible and preferablyinsoluble in the body fluids and tissues that the device comes intocontact with. In some embodiments, it is further preferred that thematerials used in fabricating the reservoir 2 are pliable materials thatallows the reservoir 2 to be folded, rolled and/or compressed forinsertion through a small incision that requires few or no sutures forclosure. Once inside the incision, the reservoir 2 may automaticallyunfold or unroll to some extent. Additionally, as agent is injectedthrough the inlet port 5 into the reservoir 2, the reservoir 2 mayunfold or unroll and expand as it is filled with the agent.

In one preferred embodiment, the reservoir 2 is in the form of a balloonand is fabricated of an elastic material. As the agent is injected intothe inlet port 5, the agent passes into the expandable reservoir 2 orballoon, thereby inflating and expanding the reservoir 2 or balloon.Pressure of the elastic material against the agent within the reservoir2 provides a driving force for delivery of agent through the deliverymechanism 6. Suitable materials for use in forming an elastic reservoirare well known and may be readily determined by one of skill in the art.For example, some suitable include thin-walled nondistensible materials,such as PET, and more elastomeric materials, such as polyurethane. Whenthe reservoir 2 is fabricated of a material such as PET, flow throughthe delivery mechanism 6 is primarily driven by diffusion and/orintraocular pressure force. When the reservoir 2 is fabricated of amaterial such as polyurethane, delivery of the agent may be driven, aleast in part, by the spring-like properties of the material forming thereservoir 2.

In one embodiment, the delivery mechanism comprises at least a portionof the reservoir 2. For example, this may be accomplished by fabricatingat least a portion of the reservoir 2 of a material that is permeable tothe agent. Such materials may vary depending on the particularapplication and the agent to be delivered and may be readily determinedby one of skill in the art. For example, this may be accomplished byfabricating at least a portion of the reservoir 2 of a material that ispermeable to the agent. Such materials may vary depending on theparticular application and the agent to be delivered and may be readilydetermined by one of skill in the art. By way of example, some suitablepermeable materials may include polycarbonates, polyolefins,polyurethanes, copolymers of acrylonitrile, copolymers of polyvinylchloride, polyamides, polysuiphones, polystyrenes, polyvinyl fluorides,polyvinyl alcohols, polyvinyl esters, polyvinyl butyrate, polyvinylacetate, polyvinylidene chlorides, polyvinylidene fluorides, polyimides,polyisoprene, polyisobutylene, polybutadiene, polyethylene, polyethers,polytetrafluoroethylene, polychloroethers, polymethylmethacrylate,polybutylmethacrylate, polyvinyl acetate, nylons, cellulose, gelatin,silicone rubbers and porous rubbers.

The particular material may be chosen to provide a particular rate ofdelivery of the agent, which may be readily determined by one of skillin the art. The rate of delivery of an agent may also be increased ordecreased by varying the percentage of the reservoir 2 formed of thematerial permeable to the agent. Preferably, to provide a slower rate ofdelivery, the reservoir 2 may be fabricated of 50% or less permeablematerial. For example, the reservoir 2 may be fabricated of 1%, 5%, 10%,20%, 30%, 40% or 50% of permeable material. For a faster rate ofdelivery, the reservoir may be fabricated of greater than 50% ofpermeable material. For example, the reservoir 2 may be fabricated of51%, 55%, 60%, 70%, 80%, 90% or 100% of permeable material.

In another embodiment, for example, as shown in FIG. 4b , the deliverymechanism 6 comprises one or more apertures 7 in the reservoir 2 formed,for example, with a laser, hot wire, drilling device or similarmechanism. The one or more apertures 7 may be located along the lengthof the reservoir 2 and/or at the distal end 4 of the reservoir 2. Thenumber and size of the one or more apertures 7 may vary depending on thedesired rate of delivery of the agent and may be readily determined byone of skill in the art.

When the delivery device 1 includes a hollow body or tube 10, the distalend 12 of the hollow body or tube 10 may extend outside the reservoir 2,as shown in FIGS. 1-3, and may serve as the delivery mechanism 6 throughwhich the agent is delivered to the treatment site. In this embodiment,one or more apertures 13 are located through the wall of the hollow bodyor tube 10 to provide communication between the contents of the hollowbody or tube 10 and the reservoir 2. Thus, as the agent is injectedthrough the proximal end 11 of the hollow body or tube 10, which formsthe inlet port 5, the agent flows through the hollow body or tube 10 andinto the reservoir 2 through the one or more apertures 13 in the wall ofthe hollow body or tube 10. Preferably, the device 1 is designed suchthat as the agent is injected into the delivery device 1, all or amajority of the agent injected through the inlet port 5 passes throughthe hollow body or tube 10 into the reservoir 2 rather than passingdirectly out of the device through the distal end of the hollow body ortube 10. This may be accomplished by, for example, providing one or moreapertures 13 in wall of the hollow body or tube 10 that are larger thanor that accommodate greater flow of agent than the delivery mechanism 6.Alternatively, a valve (not shown) or similar mechanism may be locatedat the delivery mechanism 6 for closing off the delivery mechanism 6during injection of the agent.

In a preferred embodiment, the distal end 12 of the hollow body or tube10 is designed to provide controlled delivery of agent from the device.This may be achieved by, for example, providing a distal end 12 withsmall holes and/or, for example, placing a covering or lining (notshown) over the distal end 12, wherein the covering or lining has aparticular porosity to the agent or wherein the covering or lining isfabricated of a diffusion or rate-limiting membrane, matrix material orsimilar material.

In another embodiment, wherein the distal end 12 of the hollow body ortube 10 extends outside the reservoir 2, it is also possible to designthe device such that both the distal end 12 and the reservoir 2 form thedelivery mechanism 6. Thus, for example, the distal end 12 may bedesigned as set out above to deliver the agent and, for example, thereservoir 2 may be fabricated of a permeable material or one or moreapertures 7 may be formed in the reservoir 2. Still further, it ispossible to have the distal end 12 of the hollow body or tube 10 extendoutside the reservoir 2, wherein the distal end 12 is closed off anddoes not serve as a delivery mechanism but, rather, the reservoir 2serves as the delivery mechanism 6 by, for example, fabricating thereservoir 2 of a permeable material or forming one or more apertures 7in the reservoir 2.

In another embodiment wherein the delivery device 1 includes a hollowbody or tube 10, the distal end 12 of the hollow body or tube 10 may becontained within the reservoir 2, as shown in FIGS. 4a and 4b . In thisembodiment, the delivery mechanism 6 may comprises at least a portion ofthe reservoir 2 by, for example, forming at least a portion of thereservoir 2 or the entire reservoir 2 of a material that is permeable tothe agent, or one or more apertures 7 may be fabricated in the reservoir2 as described above. In this embodiment, the distal end 12 may have anopening through which the agent travels from the inlet port 5 into thereservoir 2. At least one aperture 13 may alternatively or may also belocated along the hollow body or tube 10 through which agent may travelfrom the inlet port 5 into the reservoir 2.

The hollow body or tube 10 is preferably rigid and provides structuralsupport beneath the reservoir 2 for easier implantation of the device 1through the incision. As such, the hollow body or tube 10 may be formedof rigid materials including, for example, stainless steel, titanium,nitinol, polymers and other similar materials. As shown in FIGS. 1-4 b,the hollow body or tube 10 is preferably cylindrical in shape, with acircular cross-section. However, the shape of the hollow body or tube 10is not limited and, for example, the hollow body or tube 10 mayalternatively have, for example, square, rectangular, octagonal or othercross-sectional shapes.

The reservoir 2 is bonded to the hollow body or tube 10 forming afluid-tight seal that does not separate from the hollow body or tube 10during use, thereby preventing leakage of agent out of the devicebetween the hollow body or tube 10 and reservoir 2. Thus may beaccomplished by using a variety of adhesives and epoxies.

The inlet port 5 of the delivery device 1 is designed such that theneedle of a syringe, or similar injection mechanism, may be insertedthrough the inlet port 5 and the agent housed within the syringe orinjection mechanism may be injected through the inlet port 5 and intothe reservoir 2. The inlet port 5 preferably forms a snug seal about theneedle of the syringe or injection mechanism to prevent leakage of theagent out of the inlet port around the syringe needle or injectionmechanism and to provide sterile injection of agent into the deliverydevice 1. If desired, fittings or collars (not shown), through which asyringe needle or injection mechanism may be inserted and which form asnug seal about the syringe needle or injection mechanism, may bemounted on the inlet port 5.

Upon injection of the agent into the drug delivery device 1, the needleof the syringe or the injection mechanism is removed from the inlet port5 and the inlet port 5 sealed. This may be accomplished by providing aremovable cover (not shown) on the inlet port 5 that may be removed forinjection of the agent and replaced when the agent has been injected. Ina preferred embodiment, the inlet port 5 is composed of an injectableself-sealing material through which the needle or injection mechanismmay be inserted and which seals off automatically when the needle orinjection mechanism is removed. Such materials are known and include,for example, silicone rubber, silicone elastomers and polyolefin.

As shown in FIGS. 1-4 b, a fixation mechanism 8, such as, for example, ascleral hub, may further be located near the inlet port 5 to assist instabilizing the device 1 near the delivery site. Preferably, thedelivery device 1 is inserted into the incision until the fixationmechanism 8 abuts the incision. In one embodiment, as shown in FIGS. 1-4b, the fixation mechanism 8 is in the form of extensions from theproximal end 11 of the hollow body or tube 10. These extensions rest onthe surface surrounding the incision, as shown in FIGS. 2-3. Theseextensions may be of any shape, for example, circular, rectangular,triangular, etc. and are sized to provide a surface on which the deviceI stably rests and to provide a portion that may be sutured or otherwisesecured to the surface surrounding the incision. While the extensionsare shown as extending approximately perpendicularly from the hollowbody of tube 10, the extensions are not limited to such an arrangementand may, for example, be curved away from the device so as to conform tothe curvature in the surface of the eye. The overall shape and size ofthe fixation mechanism 8 is not limited as long as irritation and damageto the surface of the eye or other area of the body that it is incontact with are minimized.

As shown in FIG. 3, the delivery device 1 may further include a tube 14having a first end 16 and a second end 18, for the delivery oftherapeutic agent directly to a target site. For example, the first end16 of the tube 14 may be connected to the distal end 4 of the reservoir2 or the distal end 12 of the hollow body or tube 10 and the second end18 of the tube may be secured to or located proximal to the target site(e.g. the choroids and retinal pigment epithelial cells). The tube 14may be sized as so as to limit delivery rate, to minimize trauma to theretina, and to minimize leaking of the agent. The tube 14 is preferablyfabricated of a flexible material so that small movements of thedelivery device 1 will not be translated to the retina, therebyminimizing the risk of retinal tearing, detachment and other damage.

In some embodiments, it may also be desirable to deliver the agentthrough both the reservoir 2 and the tube 14. In such embodiments, forexample, in addition to a tube 14 extending from the distal end 4 of thereservoir 2 or the distal end 12 of the hollow body or tube 10, at leasta portion of the reservoir 2 may be fabricated of a material permeableto the agent or the reservoir 2 may have one or more apertures 7 throughwhich the agent may be delivered from the reservoir 2 as discussedabove.

The dimensions of the delivery device 1 will depend on the intendedapplication of the device, and will be readily apparent to those havingordinary skill in the art. By way of example, when the delivery device 1is used to deliver therapeutic agents to the eye, the device is designedfor insertion through a small incision, preferably ranging from about0.25 mm to about 1 mm in diameter, more preferably less than 0.5 mm indiameter, thereby requiring few or no sutures for scleral closure at theconclusion of the procedure. As such, the cross-section of the device 1with the reservoir 2 compressed preferably ranges from about 0.25 mm toabout 1 mm in diameter, and, more preferably, is no greater than 0.5 mm.Preferably, the hollow body or tube 10 has diameter ranging from about0.5 to about 1.0 mm, and the reservoir 2 may be compressed to the hollowbody or tube 10 so as to provide an overall cross section no greaterthan 1.0 mm. If the hollow body or tube 10 is not tubular, the largestdimension of the cross section can be used to approximate the diameterfor this purpose. When used to deliver agents to the posterior chamberof the eye, the device 1 preferably has a length ranging from about 0.5cm to about 1.5 cm such that when the fixation mechanism 8 is sutured orotherwise secured to the sclera in the region of the pars plana, thedelivery mechanism 6 is positioned near the posterior chamber of theeye.

When included in the device 1, the dimensions of the tube 14 will dependon the intended application of the device, and will be readily apparentto those having ordinary skill in the art. By way of example, when usedto deliver an agent to the choroids and retinal pigment epithelial cellsof the eye, the tube 14 is preferably sized so as to limit deliveryrate, to minimize trauma to the retina, and to minimize leaking ofagent. As such, the tube 14 preferably has a length ranging from about 1cm to about 2.5 cm, an outer diameter less than about 0.1 mm, and aninner diameter ranging from about 0.001 mm to about 0.007 mm, and morepreferably, from about 0.005 mm to about 0.001.

The use of the delivery device 1 of the present invention can be furtherunderstood from the following discussion relating to a method fortreating chronic diseases of the eye by sustained release of therapeuticagent to the eye and with reference to FIGS. 1-5.

The delivery device 1 is generally used by the following procedure: thedelivery device 1 is prepared with the reservoir 2 empty and preferablycompressed, as shown in FIGS. 1a and 4 a. If a hollow body or tube 10 isincluded in the device, the reservoir 2 is preferably compressed aboutthe hollow body or tube 10 as shown in FIG. 1 a, to provide a lowprofile that allows the delivery device 1 to be implanted and removedthrough a small access incision that requires few or no sutures forclosure. If a tube 14 is used for direct delivery of the therapeuticagent to the target site, the first end 16 of the tube 14 is connectedto the distal end 4 of the reservoir 2 or the distal end 12 of thehollow body or tube 10.

An incision is made to provide access to the treatment site. Forexample, when used to deliver therapeutic agent to the posterior chamberof the eye, a sclerotomy is created for insertion of the delivery device1. Conventional techniques may be used for the creation of thesclerotomy. Such techniques require the dissection of the conjunctiva 44and the creation of pars plana scleral incisions through the sclera 46.As shown in FIG. 5, the dissection of the conjunctiva 44 typicallyinvolves pulling back the conjunctiva 44 about the eye 42 so as toexpose large areas of the sclera 46 and the clipping or securing of theconjunctiva 44 in that pulled back state (normal position of conjunctivashown in phantom). In other words, the sclera 46 is not exposed only inthe areas where the pars plana scleral incisions are to be made.Surgical instruments used in the procedure are then passed through theseincisions. Thus, the incisions created for the procedure must be madelarge enough to accommodate the instruments required for the procedure.

Alternatively, the creation of the sclerotomy may be accomplished by useof an alignment device and method, such as that described in U.S. Ser.No. 09/523,767 the teachings of which are incorporated herein byreference, that enables sutureless surgical methods and devicestherefore. In particular, such methods and devices do not require theuse of sutures to seal the openings through which instruments areinserted. The alignment devices are inserted through the conjunctiva andsclera to form one or more entry apertures. Preferably, the alignmentdevices are metal or polyimide cannulas through which the surgicalinstruments used in the procedure are inserted into the eye.

The delivery device 1 is then inserted through the incision either byhand or using a variety of insertion devices, e.g. syringe-like devices,known to those of skill in the art. Once safely inside the eye, if thetube 14 is utilized in the application, microforceps or similarpositioning mechanisms may be used to position the tube 14 at thetreatment location.

The fixation mechanism 8 may then be sutured or otherwise secured to thesclera to hold the delivery device 1 in place. If a cover is used toclose the inlet port 5, it is removed at this time, and, if used, acollar for providing a snug fit about the syringe or other injectionmechanism is mounted on the inlet port 5. The syringe or other injectionmechanism is then connected to the inlet port 5 for injection of theagent into the delivery device 1. If the inlet port 5 is composed of aninjectable self-sealing material through which the needle of a syringeor other injection mechanism may be inserted and which seals offautomatically when the needle other injection mechanism is removed, theneedle or other injection mechanism is simply inserted through the inletport 5 and the agent injected. Following injection, the conjunctiva maybe adjusted to cover the distal end of the device.

When the device is used to deliver agents to the eye for the treatmentof a variety of ocular conditions such as, for example, retinaldetachment, occlusions, proliferative retinopathy, diabetic retinopathy,inflammations such as uveitis, choroiditis and retinitis, degenerativedisease, vascular diseases and various tumors including neoplasms, someagents suitable for delivery to the eye may include, for example,antibiotics such as tetracycline, chlortetracycline, bacitracin,neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline,chloramphenicol, rifampicin, ciprofloxacin, tobramycin, gentamycin, anderythromycin and penicillin; antifungals such as amphotericin B andmiconazole; antibacterials such as sulfonamides, sulfadiazine,sulfacetamide, sulfamethizole and sulfisoxazole, nitrofurazone andsodium propionate; antivirals, such as idoxuridine trifluorotymidine,acyclovir, ganciclovir and interferon; antibacterial agents such asnitrofurazone and sodium propionate; antiallergenics such as sodiumcromoglycate, antazoline, methapyriline, chlorpheniramine, cetirizine,pyrilamine and prophenpyridamine; anti-inflammatories such ashydrocortisone, hydrocortisone acetate, dexamethasone 21-phosphate,fluocinolone, medrysone, methylprednisolone, prednisolone 21-phosphate,prednisolone acetate, fluoromethalone, betamethasone and triamcinolone;non-steroidal anti-inflammatories such as salicylate, indomethacin,ibuprofen, diclofenac, flurbiprofen and piroxicam; decongestants such asphenylephrine, naphazoline and tetrahydrozoline; decongestants such asphenylephrine, naphazoline, and tetrahydrazoline; miotics andanti-cholinesterase such as pilocarpine, salicylate, carbachol,acetylcholine chloride, physostigmine, eserine, diisopropylfluorophosphate, phospholine iodine, and demecarium bromide; mydriaticssuch as atropine sulfate, cyclopentolate, homatropine, scopolamine,tropicamide, eucatropine, and hydroxyamphetamine; sympathomimetics suchas epinephrine; antineoplastics such as carmustine, cisplatin andfluorouracil; immunological drugs such as vaccines and immunestimulants; hormonal agents such as estrogens, estradiol,progestational, progesterone, insulin, calcitonin, parathyroid hormoneand peptide and vasopressin hypothalamus releasing factor; betaadrenergic blockers such as timolol maleate, levobunolol HCI andbetaxolol HCI; growth factors such as epidermal growth factor,fibroblast growth factor, platelet derived growth factor, transforminggrowth factor beta, somatotropin and fibronectin; carbonic anhydraseinhibitors such as dichlorophenamide, acetazolamide and methazolamide;inhibitors of angiogenesis such as angiostatin, anecortave acetate,thrombospondin, and anti-VEGF antibody; and other therapeutic agentssuch as prostaglandins, antiprostaglandins and prostaglandin precursors.

In some applications, additives may further be included in the agentand, for example, some suitable additives may include water, saline,dextrose, carriers, preservatives, stabilizing agents, wetting agents,emulsifying agents or other similar materials.

In one embodiment, wherein the delivery device 1 comprises a reservoir 2having an inlet port 5 located near the proximal end 3 of the reservoir2, the agent injected through the inlet port 5 travels into thereservoir 2. If the reservoir 2 is fabricated of an elastic material,the reservoir 2 inflates/expands as it is filled. When the agent hasbeen injected, the needle or other injection mechanism is removed fromthe inlet port 5 and the inlet port 5 sealed. The agent in the reservoir2 is then delivered gradually via the delivery mechanism 6. If tube 14is included, the agent is delivered through the tube 14 and/or reservoir2. Once the therapeutic agent had been delivered to the treatment area,the delivery device 1 may be refilled for further delivery or removed ifthe required dose of agent has been delivered for treatment of thecondition. If required, an aspirating device or similar mechanism (notshown) may be used to further compress the reservoir 2, thereby enablingremoval of the delivery device 1 through a small incision that requiresfew or no sutures are required for sclera' closure.

In the embodiment that further comprises a hollow body or tube 10, theagent injected through the inlet port 5 travels through the hollow bodyor tube 10 and into the reservoir 2 through either the one or moreapertures 13 in the hollow body or tube 10 or the distal end 12 of thehollow body or tube. The needle or other injection mechanism is thenremoved from the inlet port 5 and the inlet port 5 sealed. The agent inthe reservoir 2 is then delivered to the treatment area graduallythrough the reservoir 2 and/or through the distal end 12 of the hollowbody or tube 10. If tube 14 is included, the agent is delivered throughthe tube 14 and/or reservoir 2. Once the therapeutic agent had beendelivered to the treatment area, the delivery device 1 may be refilledfor further delivery or removed if the required dose of agent has beendelivered for treatment of the condition. If required, an aspiratingdevice or similar mechanism (not shown) may be used to further compressthe reservoir 2 about the hollow body or tube 10, thereby enablingremoval of the delivery device 1 through a small incision that requiresfew or no sutures are required for scleral closure.

The invention is not be limited to ocular applications, and isparticularly useful in other limited access regions such as the innerear.

The present invention also includes kits that comprise one or moredevice of the invention, preferably packaged in sterile condition. Kitsof the invention also may include, for example, one or more tubes 14,one or more reservoirs 2, means for suturing or securing the fixationmechanism 8 to the sclera, etc. for use with the device, preferablypackaged in sterile condition, and/or written instructions for use ofthe device and other components of the kit.

All documents mentioned herein are incorporated by reference herein intheir entirety.

The foregoing description of the invention is merely illustrativethereof, and it is understood that variations and modifications can beeffected without departing from the scope or spirit of the invention asset forth in the following claims.

What is claimed is:
 1. A method of delivering at least a firsttherapeutic agent into an interior chamber of a patient's eye having anocular disorder, comprising: inserting a distal portion of an implantthrough a sclera of the eye and into the interior chamber, the implantcomprising: a refillable reservoir made of one or more biocompatiblematerials and adapted to contain the first therapeutic agent, thereservoir comprising a proximal portion and a distal portion, the distalportion comprising a non-permeable body having multiple apertures formedthrough the body, such that, when implanted, the first therapeutic agentflows or diffuses through the apertures into the eye, wherein themultiple apertures are adapted to achieve a desired rate of controlled,sustained delivery of the first therapeutic agent to the eye to treatthe disorder; and an inlet portion coupled to the proximal portion ofthe reservoir and in fluid communication with the reservoir, the inletportion being injectable and capable of self-sealing upon retraction ofa needle, the inlet portion adapted, when implanted, to remain externalto and adjacent the sclera; wherein at least the distal portion of thereservoir extends into the eye upon insertion; and treating the disorderfor an initial treatment period of time through the controlled,sustained delivery of the first therapeutic agent.
 2. The method ofclaim 1, further comprising introducing a needle through the inletportion to aspirate the reservoir.
 3. The method of claim 1, wherein thepatient's eye comprises a vitreous cavity, wherein the distal portion ofthe implant is inserted into the vitreous cavity, and wherein the agentflows or diffuses into vitreous in the cavity through the apertures. 4.The method of claim 1, further comprising removing the implant from theeye after a desired dose of agent has been delivered, and closing ascleral incision.
 5. The method of claim 4, wherein the scleral incisionrequires few or no sutures to close the sclera upon removal.
 6. Themethod of claim 1, wherein the implant is sufficiently structurallyrigid to facilitate insertion into the eye.
 7. The method of claim 6,wherein the rigidity is provided to the implant by at least one ofstainless steel, titanium and nitinol.
 8. The method of claim 1, whereineach of the apertures is formed in the reservoir by laser, hot wire,drilling device or similar mechanism.
 9. The method of claim 1,whereinthe inlet portion comprises a scleral hub.
 10. The method of claim 9,wherein the scleral hub is circular.
 11. The method of claim 9, whereinthe scleral hub conforms to a curvature of the eye.
 12. The method ofclaim 1, further comprising, after the initial treatment period,injecting additional therapeutic agent into the reservoir through theinlet portion, to continue to treat the patient for an additionaltreatment period without removing the implant from the eye.
 13. Themethod of claim 1, wherein each of the apertures has a lengthcorresponding to a thickness of a wall of the body of the reservoir. 14.The method of claim 12, wherein the additional therapeutic agentcomprises a second therapeutic agent different from the firsttherapeutic agent.
 15. The method of claim 1, wherein the multipleapertures are adapted to achieve the desired rate of controlled,sustained delivery by varying at least one of the number and size of theapertures.
 16. The method of claim 1, wherein the distal portion of thereservoir is non-permeable to the therapeutic agent.
 17. The method ofclaim 16, wherein the non-permeable portion comprises at least 90% ofthe surface area of the reservoir.
 18. The method of claim 1, whereinthe distal portion of the implant is roughly cylindrical upon insertioninto the eye.
 19. The method of claim 1, wherein the desired rate ofcontrolled, sustained delivery of the agent is determined based on anindividual need of the patient.
 20. The method of claim 12, wherein theinjecting additional agent is performed if further dose of agent isrequired for treatment of the disorder.